The subject invention relates to organic compounds which have useful therapeutic properties. More particularly, the invention concerns compounds having antiproliferative activity. The subject invention further provides pharmaceutical compositions comprising such compounds, methods for the preparation of the compounds, and methods for their use for therapeutic purposes.
Considerable research and resources have been devoted to anti-proliferative measures, including chemotherapy. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling the growth of unwanted cells such as tumors, new methods and antiproliferative compositions are needed.
In searching for new biologically active compounds, it has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activity of great diversity. For example, the diterpene commonly known as taxol, isolated from several species of yew trees, is a mitotic spindle poison that stabilizes microtubules and inhibits their depolymerization to free tubulin (Fuchs, D. A., R. K. Johnson [1978] Cancer Treat. Rep. 62:1219-1222; Schiff, P. B., J. Fant, S. B. Horwitz [1979] Nature (London) 22:665-667). Taxol is also known to have antitumor activity and has undergone a number of clinical trials which have shown it to be effective in the treatment of a wide range of cancers (Rowinski, E. K. R. C. Donehower [1995] N. Engl. J Med. 332:1004-1014). See also, e.g., U.S. Pat. Nos. 5,157,049; 4,960,790; and 4,206,221.
Marine sponges have also proven to be a source of biologically active chemical molecules. A number of publications have been issued disclosing organic compounds derived from marine sponges including Scheuer, P. J. (ed.) Marine Natural Products, Chemical and Biological Perspectives, Academic Press, New York, 1978-1983, Vol. I-V; Uemura, D., K. Takahashi, T. Yamamoto, C. Katayama, J. Tanaka, Y. Okumura, Y. Hirata (1985) J. Am. Chem. Soc. 107:4796-4798; Minale, L. et al. (1976) Fortschr. Chem. org. Naturst. 33:1-72; Faulkner, D. J. (1987) Natural Products Reports 4:539-576, and references cited therein. See, also U.S. Pat. Nos. 4,939,168, 5,010,099, 5,681,847 and 5,840,750.
The microsclerodermins are a class of naturally occurring cyclic peptides which possess unusual amino acids. Five compounds in the class have been disclosed in the literature, microsclerodermins A-E. These compounds have been isolated from sponges of the genus Microscleroderma and Theonella and have been disclosed to have potent antifungal activity. See for example: Bewley, Debitus and Faulkner, xe2x80x9cMicrosclerodermins A and B, Antifungal Cyclic Peptides from the Lithistid Sponge Microscleroderma, in Journal of the American Chemical Society, 1994, 116, 7631-7636 and also Schmidt and Faulkner, xe2x80x9cMicrosclerodermins C-E, Antifungal Cyclic Peptides from the Lithistid marine Sponges Theonella and Microscleroderma, Tetrahedron 1998 54, 3043-3056.
The present invention has added to the arsenal of antitumor compounds by the discovery of a new class of organic compounds possessing, inter alia, useful tubulin-matrix modifying and antitumor activities.
The subject invention provides materials and methods useful in the treatment of unwanted cellular proliferation. Such unwanted cellular proliferation may be associated with, for example, autoimmune disorders, inflammation, and tumors or other forms of cancer. Specifically exemplified herein is the use of microsclerodermin compounds for the control of tumors.
One aspect of the current invention concerns the compound designated microsclerodermin F. Advantageously, microsclerodermin F possesses potent antiproliferative activity against mammalian tumor cells. In a specific example, A549 human lung adenocarcinoma cells treated with microsclerodermin F do not undergo mitosis and show pronounced changes in the normal arrangement of microtubules within the cell.
A further aspect of the subject invention pertains to methods for controlling unwanted cellular proliferation using the compounds of the subject invention. Yet another aspect of the subject invention pertains to compositions, comprising the compounds of the subject invention, wherein these compositions can be used to inhibit unwanted cellular proliferation.
The antiproliferative effect of the compounds of the subject invention could not be predicted based upon either the structures of the compounds or upon the previously reported antifungal activity. The use of these compounds provides a novel opportunity for intervention in proliferative diseases such as cancer.